Theo Nash
Carboxylic acids can be converted to secondary alcohols through a few different methods. One method involves first converting the carboxylic acid to a ketone and then reducing it to an alcohol. This can be achieved using 2eq of organolithium followed by reduction. Another method involves converting the carboxylic acid to an acid chloride and then alkylating it with an organocuprate (Gilman reagent), followed by reduction. Additionally, the use of borane ($\ce{BH3}$) is effective for the selective reduction of carboxyl groups, and it is compatible with many other groups.
| Characteristics | Values |
|---|---|
| Conversion Method | Oxidation of alcohols |
| Conversion Example | Conversion of methanoic/formic acid to methanol |
| Reagents | Borane, LiAlH4, NaOtBu-O2, CrO3, TEMPO, NaOCl |
| Catalysts | 2-chloroanthraquinone, Ruthenium complex, Copper catalyst, Bismuth(III) oxide |
| Reaction Conditions | Visible light irradiation in an air atmosphere, Wet MeCN, Chemoselective oxidation |
| Yields | High yields, >90% yield |
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What You'll Learn
Convert carboxylic acid to a ketone, then reduce to alcohol
Carboxylic acids can be converted to ketones and then reduced to alcohols. This is a two-step process, and there are several methods to achieve this. Firstly, carboxylic acids can be converted to ketones through oxidation. One method is to use a dehydrogenative reaction in the presence of hydroxide and the ruthenium complex [RuCl2(IPr)(p-cymene)] as a catalyst. This will result in the desired ketone. Another method is to use a CrO3-catalysed oxidation of primary alcohols to give carboxylic acids in excellent yield.
Once the carboxylic acid has been converted to a ketone, the ketone can be reduced to an alcohol. Ketones are less reactive than aldehydes due to greater steric effects and the presence of an extra alkyl group. This makes the C=O bond less electrophilic. To reduce a ketone to an alcohol, a reducing agent is required. One commonly used reducing agent is sodium borohydride, NaBH4, due to its safety and ease of handling. However, it is important to note that NaBH4 is not strong enough to reduce carboxylic acids. Therefore, a stronger reducing agent, such as lithium aluminium hydride, LiAlH4, is needed for the reduction of carboxylic acids. LiAlH4 is much more reactive than NaBH4 but also more dangerous, as it reacts violently with water and decomposes explosively when heated above 120 °C.
Another method to reduce ketones to alcohols is through catalytic hydrogenation, such as in the Clemmensen reduction or Wolff-Kishner reduction. The choice of reducing agent and reaction conditions will depend on the specific starting materials and target molecules. It is also important to note that primary alcohols can be made by the hydride reduction of aldehydes, carboxylic acids, or esters, while secondary alcohols are made by the reduction of ketones.
Overall, the process of converting carboxylic acids to ketones and then reducing them to alcohols involves multiple steps and requires careful selection of reagents and reaction conditions. The specific procedure will depend on the desired outcome and the available materials.
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Use 2eq of organolithium, then reduction
Carboxylic acids can be converted to alcohols using organolithium reagents. This reaction involves adding two equivalents of an organolithium reagent to a carboxylic acid, resulting in the formation of a ketone. This reaction is exclusive to organolithium reagents and will not work with Grignard reagents.
The first step is the deprotonation of the carboxylic acid by the organolithium species, which acts as a strong base. This is followed by the addition of another equivalent of the organolithium reagent to the carbonyl carbon. The resulting di-anion is stable in solution until an acid is added during the workup, leading to the formation of a hydrate.
The key reaction in this process is the addition of the organolithium reagent to the deprotonated carboxylic acid, forming a stable tetrahedral intermediate. After the addition of the second equivalent of the organolithium reagent, the reaction is complete until the workup with a mild acid. The negatively charged oxygen ("alkoxide") is then protonated with the mild acid to yield the final alcohol product.
It is important to note that Grignard and organolithium reagents are powerful bases. Consequently, they cannot be used as nucleophiles on compounds containing acidic hydrogens, as they will act as bases and deprotonate the acidic hydrogen rather than behaving as nucleophiles.
In summary, the conversion of carboxylic acids to alcohols using organolithium reagents involves deprotonation, addition of a second equivalent of the reagent, and subsequent protonation with a mild acid to produce the desired alcohol. This process is a useful synthetic tool for transforming carboxylic acids into their corresponding alcohols.
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Convert to nitrile, then Grignard addition
Carboxylic acids can be prepared by the conversion of nitriles, which are then subjected to Grignard addition. This method is particularly useful when the reactant contains a primary halogen, which can be converted to a nitrile through an SN2 reaction with NaCN. The resulting nitrile can then be hydrolyzed to form a carboxylic acid. This is a two-step process, where the nitrile first reacts with water to produce an amide, which then forms an ammonium salt of a carboxylic acid.
The Grignard reaction involves the addition of an alkyl, allyl, vinyl, or aryl-magnesium halide (Grignard reagent) to a carbonyl group in an aldehyde or ketone. The Grignard reagent adds to the C=O bond of carbon dioxide (an electrophile), yielding a halomagnesium carboxylate salt of a carboxylic acid. This reaction is generally thought to proceed through a nucleophilic addition mechanism.
The Grignard reaction can be used to convert nitriles to alcohols. For example, 3-bromopropan-1-ol, a primary alkyl halide, can be converted into 4-hydroxybutanoic acid by first converting it into a nitrile and then hydrolyzing it. Similarly, o-hydroxybenzyl bromide, another primary alkyl halide, can be converted into o-hydroxyphenylacetic acid through the same process.
The Grignard reaction is a versatile synthetic tool, allowing for the addition of a carbon atom and accommodating tertiary halides without significant steric hindrance. It is compatible with a wide range of functional groups, making it a valuable method for the synthesis of carboxylic acids from nitriles.
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Convert to acid chloride, then alkylate with an organocuprate
To convert a carboxylic acid to an alcohol, one method is to first convert the carboxylic acid to an acid chloride, and then alkylate with an organocuprate (also known as a Gilman reagent).
Converting a carboxylic acid to an acid chloride can be done by using a variety of reagents, such as SOCl2, PCl3, SOBr2, and PBr3. These reagents replace the hydroxyl group of the carboxylic acid with a chloride, forming the acid chloride.
The acid chloride can then undergo a nucleophilic acyl substitution reaction with an organocuprate reagent to form a ketone. Organocuprates are less reactive than Grignard reagents because the alkyl groups are connected to copper rather than magnesium, making their carbanionic character less pronounced. This is due to the C−Cu bond being less polarized than a C−Mg bond.
The key step in this conversion is the formation of the acid chloride, which then allows for the subsequent reaction with the organocuprate to form the desired alcohol product.
It is important to note that the choice of reagents and reaction conditions may vary depending on the specific structure of the carboxylic acid and the desired alcohol product.
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Use borane to reduce carboxylic acid salts
Carboxylic acid salts can be rapidly reduced to their corresponding alcohols with the help of borane. This reduction is made possible by the presence of small quantities of in situ-generated BH3, which plays a crucial role in the process. The borane reduction of carboxylic acids is a mild and chemoselective method that can be used even in the presence of more nucleophilic and electrophilic functional groups. This method is advantageous because it can leave other functional groups, such as ketones, esters, nitro groups, olefins, nitriles, and amides, untouched.
The mechanism behind this transformation has been a topic of interest and discussion, with Henry Rzepa, Emeritus Professor of Computational Chemistry at Imperial College London, exploring it in a blog post. The post highlights the unique ability of borane to reduce carboxylic acids but not their esters, and the key role of borane (BH3) in the process.
Furthermore, the reduction process is not limited to a specific type of carboxylic acid. It has been demonstrated to work with various carboxylic acid-containing molecules, including drugs such as Naproxen, Ketoprofen, Indomethacin, and Isoxepac. This versatility underscores the broad applicability of the borane reduction method.
In terms of specific reaction conditions, the use of two molar equivalents of borane in tetrahydrofuran (THF) has been mentioned as a suitable approach for the rapid reduction of carboxylic acid salts to alcohols. This reaction occurs via a possible mechanism involving acyloxyborane. Additionally, the presence of alcoholic potassium hydroxide can facilitate the formation of enol ethers or ketals, further expanding the range of products accessible through this reduction process.
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Frequently asked questions
The general process involves first converting the carboxylic acid to a ketone and then reducing it to an alcohol.
One method is to use 2eq of organolithium and then perform a reduction. Another method is to convert the acid to an acid chloride and then alkylate it with an organocuprate (Gilman reagent) before performing a reduction.
One method is to use borane (BH3) which is particularly good for carboxyl groups and permits selective reduction in the presence of many other groups. Another method is to use LiAlH4 followed by hydrolysis.
